Device and method for providing phototherapy to the brain

ABSTRACT

A therapy apparatus for treating a patient&#39;s brain is provided. The therapy apparatus includes a light source having an output emission area positioned to irradiate a portion of the brain with an efficacious power density and wavelength of light. The therapy apparatus further includes an element interposed between the light source and the patient&#39;s scalp. The element is adapted to inhibit temperature increases at the scalp caused by the light.

CLAIM OF PRIORITY

This application is a continuation of U.S. patent application Ser. No.10/682,379, filed Oct. 9, 2003, and which claims benefit to U.S.Provisional Application No. 60/442,693, filed Jan. 24, 2003 and U.S.Provisional Application No. 60/487,979, filed Jul. 17, 2003, and whichis a continuation-in-part of U.S. patent application Ser. No.10/287,432, filed Nov. 1, 2002, which claims benefit to U.S. ProvisionalApplication No. 60/336,436, filed Nov. 1, 2001 and U.S. ProvisionalApplication No. 60/369,260, filed Apr. 2, 2002. U.S. patent applicationSer. No. 10/682,379 and 10/287,432 and U.S. Provisional Application Nos.60/442,693, 60/487,979, 60/336,436, and 60/369,260 are incorporated intheir entireties by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates in general to phototherapy, and moreparticularly, to novel apparatuses and methods for phototherapy of braintissue affected by stroke.

2. Description of the Related Art

Stroke, also called cerebrovascular accident (CVA), is a suddendisruption of blood flow to a discrete area of the brain that is broughton by a clot lodging in an artery supplying that area of that brain, orby a cerebral hemorrhage due to a ruptured aneurysm or a burst artery.The consequence of stroke is a loss of function in the affected brainregion and concomitant loss of bodily function in areas of the bodycontrolled by the affected brain region. Depending upon the extent andlocation of the primary insult in the brain, loss of function variesgreatly from mild or severe, and may be temporary or permanent.Lifestyle factors such as smoking, diet, level of physical activity andhigh cholesterol increase the risk of stroke, and thus stroke is a majorcause of human suffering in developed nations. Stroke is the thirdleading cause of death in most developed nations, including the UnitedStates.

Until recently, stroke treatment was restricted to providing basic lifesupport at the time of the stroke, followed by rehabilitation. Recently,new drug therapies have taken the approach of breaking up blood clots orprotecting surviving at-risk neurons from further damage.

Thrombolytic therapy includes aspirin or intravenous heparin to preventfurther clot formation and to maintain blood flow after an ischemicstroke. Thrombolytic drugs include tissue plasminogen activator (TPA)and genetically engineered versions thereof, and streptokinase. However,streptokinase does not appear to improve the patient's outlook unlessadministered early (within three hours of stroke). TPA when administeredearly appears to substantially improve prognosis, but slightly increasesthe risk of death from hemorrhage. In addition, over half of strokepatients arrive at the hospital more than three hours after a stroke,and even if they arrive quickly, a CT scan must first confirm that thestroke is not hemorrhagic, which delays administration of the drug.Also, patients taking aspirin or other blood thinners and patients withclotting abnormalities should not be given TPA.

Neuroprotective drugs target surviving but endangered neurons in a zoneof risk surrounding the area of primary infarct. Such drugs are aimed atslowing down or preventing the death of such neurons, to reduce theextent of brain damage. Certain neuroprotective drugs areanti-excitotoxic, i.e., work to block the excitotoxic effects ofexcitatory amino acids such as glutamate that cause cell membrane damageunder certain conditions. Other drugs such as citicoline work byrepairing damaged cell membranes. Lazaroids such as Tirilazed (Freedox)counteract oxidative stress produced by oxygen-free radicals producedduring stroke. Other drugs for stroke treatment include agents thatblock the enzyme known as PARP, and calcium-channel blockers such asnimodipine (Nimotop) that relax the blood vessels to prevent vascularspasms that further limit blood supply. However, the effect ofnimodipine is reduced if administered beyond six hours after a strokeand it is not useful for ischemic stroke. In addition, drug therapyincludes the risk of adverse side effects and immune responses.

Surgical treatment for stroke includes carotid endarterectomy, whichappears to be especially effective for reducing the risk of strokerecurrence for patients exhibiting arterial narrowing of more than 70%.However, endarterectomy is highly invasive, and risk of strokerecurrence increases temporarily after surgery. Experimental stroketherapies include an angiography-type or angioplasty-type procedureusing a thin catheter to remove or reduce the blockage from a clot.However, such procedures have extremely limited availability andincrease the risk of embolic stroke. Other surgical interventions, suchas those to repair an aneurysm before rupture remain controversialbecause of disagreement over the relative risks of surgery versusleaving the aneurysm untreated.

Against this background, a high level of interest remains in finding newand improved therapeutic apparatuses and methods for the treatment ofstroke. In particular, a need remains for relatively inexpensive andnon-invasive approaches to treating stroke that also avoid thelimitations of drug therapy.

SUMMARY OF THE INVENTION

One aspect of the present invention provides a therapy apparatus fortreating a patient's brain. The therapy apparatus comprises a lightsource having an output emission area positioned to irradiate a portionof the brain with an efficacious power density and wavelength of light.The therapy apparatus further comprises an element interposed betweenthe light source and the patient's scalp. The element is adapted toinhibit temperature increases at the scalp caused by the light.

Another aspect of the present invention provides a therapy apparatus fortreating brain tissue. The therapy apparatus comprises a light sourcepositioned to irradiate at least a portion of a patient's head withlight. The light has a wavelength and power density which penetrates thecranium to deliver an efficacious amount of light to brain tissue. Thetherapy apparatus further comprises a material which inhibitstemperature increases of the head.

Another aspect of the present invention provides a therapy apparatus fortreating a patient's brain. The therapy apparatus comprises a lightsource adapted to irradiate at least a portion of the brain with anefficacious power density and wavelength of light. The therapy apparatusfurther comprises an element adapted to inhibit temperature increases atthe scalp. At least a portion of the element is in an optical path ofthe light from the light source to the scalp.

Another aspect of the present invention provides a therapy apparatus fortreating a patient's brain. The therapy apparatus comprises a lightsource adapted to irradiate at least a portion of the brain with anefficacious power density and wavelength of light. The therapy apparatusfurther comprises a controller for energizing said light source so as toselectively produce a plurality of different irradiation patterns on thepatient's scalp. Each of said irradiation patterns is comprised of atleast one illumination area that is small compared to the patient'sscalp, and at least one non-illuminated area.

Another aspect of the present invention provides a method comprisinginterposing a head element between a light source and the patient'sscalp. The element is comprised of a material which, for an efficaciouspower density at the brain, inhibits temperature increases at the scalp.

Another aspect of the present invention provides a therapy apparatus fortreating a patient's brain. The therapy apparatus comprises a lightsource adapted to irradiate at least a portion of the brain with anefficacious power density and wavelength of light. The therapy apparatusfurther comprises a biomedical sensor configured to provide real-timefeedback information. The therapy apparatus further comprises acontroller coupled to the light source and the biomedical sensor. Thecontroller is configured to adjust said light source in response to thereal-time feedback information.

Another aspect of the present invention provides a method of treatingbrain tissue. The method comprises introducing light of an efficaciouspower density onto brain tissue by directing light through the scalp ofa patient. Directing the light comprises providing a sufficiently largespot size on said scalp to reduce the power density at the scalp belowthe damage threshold of scalp tissue, while producing sufficient opticalpower at said scalp to achieve said efficacious power density at saidbrain tissue.

Another aspect of the present invention provides a method of treating apatient's brain. The method comprises covering at least a significantportion of the patient's scalp with a light-emitting blanket.

Another aspect of the present invention provides a method of treating apatient's brain following a stroke. The method comprises applyinglow-level light therapy to the brain no earlier than several hoursfollowing said stroke.

Another aspect of the present invention provides a method for treating apatient's brain. The method comprises introducing light of anefficacious power density onto a target area of the brain by directinglight through the scalp of the patient. The light has a plurality ofwavelengths and the efficacious power density is at least 0.01 mW/cm² atthe target area.

Another aspect of the present invention provides a method for treating apatient's brain. The method comprises directing light through the scalpof the patient to a target area of the brain concurrently with applyingan electromagnetic field to the brain. The light has an efficaciouspower density at the target area and the electromagnetic field has anefficacious field strength.

Another aspect of the present invention provides a method for treating apatient's brain. The method comprises directing an efficacious powerdensity of light through the scalp of the patient to a target area ofthe brain concurrently with applying an efficacious amount of ultrasonicenergy to the brain.

Anther aspect of the present invention provides a method of providing aneuroprotective effect in a patient that had an ischemic event in thebrain. The method comprises identifying a patient who has experienced anischemic event in the brain. The method further comprises estimating thetime of the ischemic event. The method further comprising commencingadministration of a neuroprotective effective amount of light energy tothe brain no less than about two hours following the time of theischemic event.

For purposes of summarizing the present invention, certain aspects,advantages, and novel features of the present invention have beendescribed herein above. It is to be understood, however, that notnecessarily all such advantages may be achieved in accordance with anyparticular embodiment of the present invention. Thus, the presentinvention may be embodied or carried out in a manner that achieves oroptimizes one advantage or group of advantages as taught herein withoutnecessarily achieving other advantages as may be taught or suggestedherein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically illustrates a therapy apparatus comprising a capwhich fits securely over the patient's head.

FIG. 2 schematically illustrates a fragmentary cross-sectional viewtaken along the lines 2-2 of FIG. 1, showing one embodiment of a portionof a therapy apparatus comprising an element and its relationship to thescalp and brain.

FIG. 3 schematically illustrates an embodiment with an elementcomprising a container coupled to an inlet conduit and an outlet conduitfor the transport of a flowing material through the element.

FIG. 4A schematically illustrates a fragmentary cross-sectional viewtaken along the lines 2-2 of FIG. 1, showing another embodiment of aportion of a therapy apparatus comprising an element with a portioncontacting the scalp and a portion spaced away from the scalp.

FIG. 4B schematically illustrates a fragmentary cross-sectional viewtaken along the lines 2-2 of FIG. 1, showing an embodiment of a portionof a therapy apparatus comprising a plurality of light sources and anelement with portions contacting the scalp and portions spaced away fromthe scalp.

FIGS. 5A and 5B schematically illustrate cross-sectional views of twoembodiments of the element in accordance with FIG. 4B taken along theline 4-4.

FIGS. 6A-6C schematically illustrate an embodiment in which the lightsources are spaced away from the scalp.

FIGS. 7A and 7B schematically illustrate the diffusive effect on thelight by the element.

FIGS. 8A and 8B schematically illustrate two light beams havingdifferent cross-sections impinging a patient's scalp and propagatingthrough the patient's head to irradiate a portion of the patient's braintissue.

FIG. 9A schematically illustrates a therapy apparatus comprising a capand a light source comprising a light blanket.

FIGS. 9B and 9C schematically illustrate two embodiments of the lightblanket.

FIG. 10 schematically illustrates a therapy apparatus comprising aflexible strap and a housing.

FIG. 11 schematically illustrates a therapy apparatus comprising ahandheld probe.

FIG. 12 is a block diagram of a control circuit comprising aprogrammable controller.

FIG. 13 schematically illustrates a therapy apparatus comprising a lightsource and a controller.

FIG. 14 schematically illustrates a light source comprising a laserdiode and a galvometer with a mirror and a plurality of motors.

FIGS. 15A and 15B schematically illustrate two irradiation patterns thatare spatially shifted relative to each other.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Low level light therapy (“LLLT”) or phototherapy involves therapeuticadministration of light energy to a patient at lower power outputs thanthose used for cutting, cauterizing, or ablating biological tissue,resulting in desirable biostimulatory effects while leaving tissueundamaged. In non-invasive phototherapy, it is desirable to apply anefficacious amount of light energy to the internal tissue to be treatedusing light sources positioned outside the body. (See, e.g., U.S. Pat.No. 6,537,304 to Oron and U.S. patent application Ser. No. 10/353,130,both of which are incorporated in their entireties by reference herein.)However, absorption of the light energy by intervening tissue can limitthe amount of light energy delivered to the target tissue site, whileheating the intervening tissue. In addition, scattering of the lightenergy by intervening tissue can limit the power density or energydensity delivered to the target tissue site. Brute force attempts tocircumvent these effects by increasing the power and/or power densityapplied to the outside surface of the body can result in damage (e.g.,burning) of the intervening tissue.

Non-invasive phototherapy methods are circumscribed by setting selectedtreatment parameters within specified limits so as to preferably avoiddamaging the intervening tissue. A review of the existing scientificliterature in this field would cast doubt on whether a set ofundamaging, yet efficacious, parameters could be found. However, certainembodiments, as described herein, provide devices and methods which canachieve this goal.

Such embodiments may include selecting a wavelength of light at whichthe absorption by intervening tissue is below a damaging level. Suchembodiments may also include setting the power output of the lightsource at very low, yet efficacious, power densities (e.g., betweenapproximately 100 μW/cm² to approximately 10 W/cm²) at the target tissuesite, and time periods of application of the light energy at a fewseconds to minutes to achieve an efficacious energy density at thetarget tissue site being treated. Other parameters can also be varied inthe use of phototherapy. These other parameters contribute to the lightenergy that is actually delivered to the treated tissue and may play keyroles in the efficacy of phototherapy. In certain embodiments, theirradiated portion of the brain can comprise the entire brain.

Element to Inhibit Temperature Increases at the Scalp

FIGS. 1 and 2 schematically illustrate an embodiment of a therapyapparatus 10 for treating a patient's brain 20. The therapy apparatus 10comprises a light source 40 having an output emission area 41 positionedto irradiate a portion of the brain 20 with an efficacious power densityand wavelength of light. The therapy apparatus 10 further comprises anelement 50 interposed between the light source 40 and the patient'sscalp 30. The element 50 is adapted to inhibit temperature increases atthe scalp 30 caused by the light.

As used herein, the term “element” is used in its broadest sense,including, but not limited to, as a reference to a constituent ordistinct part of a composite device. In certain embodiments, the element50 is adapted to contact at least a portion of the patient's scalp 30,as schematically illustrated in FIGS. 1-4. In certain such embodiments,the element 50 is in thermal communication with and covers at least aportion of the scalp 30. In other embodiment, the element 50 is spacedaway from the scalp 30 and does not contact the scalp 30.

In certain embodiments, the light passes through the element 50 prior toreaching the scalp 30 such that the element 50 is in the optical path oflight propagating from the light source 40, through the scalp 30,through the bones, tissues, and fluids of the head (schematicallyillustrated in FIG. 1 by the region 22), to the brain 20. In certainembodiments, the light passes through a transmissive medium of theelement 50, while in other embodiments, the light passes through anaperture of the element 50. As described more fully below, the element50 may be utilized with various embodiments of the therapy apparatus 10.

In certain embodiments, the light source 40 is disposed on the interiorsurface of a cap 60 which fits securely over the patient's head. The cap60 provides structural integrity for the therapy apparatus 10 and holdsthe light source 40 and element 50 in place. Exemplary materials for thecap 60 include, but are not limited to, metal, plastic, or othermaterials with appropriate structural integrity. The cap 60 may includean inner lining 62 comprising a stretchable fabric or mesh material,such as Lycra or nylon. In certain embodiments, the light source 40 isadapted to be removably attached to the cap 60 in a plurality ofpositions so that the output emission area 41 of the light source 40 canbe advantageously placed in a selected position for treatment of astroke or CVA in any portion of the brain 20. In other embodiments, thelight source 40 can be an integral portion of the cap 60.

The light source 40 illustrated by FIGS. 1 and 2 comprises at least onepower conduit 64 coupled to a power source (not shown). In someembodiments, the power conduit 64 comprises an electrical conduit whichis adapted to transmit electrical signals and power to an emitter (e.g.,laser diode or light-emitting diode). In certain embodiments, the powerconduit 64 comprises an optical conduit (e.g., optical waveguide) whichtransmits optical signals and power to the output emission area 41 ofthe light source 40. In certain such embodiments, the light source 40comprises optical elements (e.g., lenses, diffusers, and/or waveguides)which transmit at least a portion of the optical power received via theoptical conduit 64. In still other embodiments, the therapy apparatus 10contains a power source (e.g., a battery) and the power conduit 64 issubstantially internal to the therapy apparatus 10.

In certain embodiments, the patient's scalp 30 comprises hair and skinwhich cover the patient's skull. In other embodiments, at least aportion of the hair is removed prior to the phototherapy treatment, sothat the therapy apparatus 10 substantially contacts the skin of thescalp 30.

In certain embodiments, the element 50 is adapted to contact thepatient's scalp 30, thereby providing an interface between the therapyapparatus 10 and the patient's scalp 30. In certain such embodiments,the element 50 is coupled to the light source 40 and in other suchembodiments, the element is also adapted to conform to the scalp 30, asschematically illustrated in FIG. 1. In this way, the element 50positions the output emission area 41 of the light source 40 relative tothe scalp 30. In certain such embodiments, the element 50 ismechanically adjustable so as to adjust the position of the light source40 relative to the scalp 30. By fitting to the scalp 30 and holding thelight source 40 in place, the element 50 inhibits temperature increasesat the scalp 30 that would otherwise result from misplacement of thelight source 40 relative to the scalp 30. In addition, in certainembodiments, the element 50 is mechanically adjustable so as to fit thetherapy apparatus 10 to the patient's scalp 30.

In certain embodiments, the element 50 provides a reusable interfacebetween the therapy apparatus 10 and the patient's scalp 30. In suchembodiments, the element 50 can be cleaned or sterilized between uses ofthe therapy apparatus, particularly between uses by different patients.In other embodiments, the element 50 provides a disposable andreplaceable interface between the therapy apparatus 10 and the patient'sscalp 30. By using pre-sterilized and pre-packaged replaceableinterfaces, certain embodiments can advantageously provide sterilizedinterfaces without undergoing cleaning or sterilization processingimmediately before use.

In certain embodiments, the element 50 comprises a container (e.g., acavity or bag) containing a material (e.g., gel). The container can beflexible and adapted to conform to the contours of the scalp 30. Otherexemplary materials contained in the container of the element 50include, but are not limited to, thermal exchange materials such asglycerol and water. The element 50 of certain embodiments substantiallycovers the entire scalp 30 of the patient, as schematically illustratedin FIG. 2. In other embodiments, the element 50 only covers a localizedportion of the scalp 30 in proximity to the irradiated portion of thescalp 30.

In certain embodiments, at least a portion of the element 50 is withinan optical path of the light from the light source 40 to the scalp 30.In such embodiments, the element 50 is substantially opticallytransmissive at a wavelength of the light emitted by the output emissionarea 41 of the light source 40 and is adapted to reduce back reflectionsof the light. By reducing back reflections, the element 50 increases theamount of light transmitted to the brain 20 and reduces the need to usea higher power light source 40 which may otherwise create temperatureincreases at the scalp 30. In certain such embodiments, the element 50comprises one or more optical coatings, films, layers, membranes, etc.in the optical path of the transmitted light which are adapted to reduceback reflections.

In certain such embodiments, the element 50 reduces back reflections byfitting to the scalp 30 so as to substantially reduce air gaps betweenthe scalp 30 and the element 50 in the optical path of the light. Therefractive-index mismatches between such an air gap and the element 50and/or the scalp 30 would otherwise result in at least a portion of thelight propagating from the light source 40 to the brain 20 to bereflected back towards the light source 40.

In addition, certain embodiments of the element 50 comprise a materialhaving, at a wavelength of light emitted by the light source 40, arefractive index which substantially matches the refractive index of thescalp 30 (e.g., about 1.3), thereby reducing anyindex-mismatch-generated back reflections between the element 50 and thescalp 30. Examples of materials with refractive indices compatible withembodiments described herein include, but are not limited to, glycerol,water, and silica gels. Exemplary index-matching gels include, but arenot limited to, those available from Nye Lubricants, Inc. of Fairhaven,Mass.

In certain embodiments, the element 50 is adapted to cool the scalp 30by removing heat from the scalp 30 so as to inhibit temperatureincreases at the scalp 30. In certain such embodiments, the element 50comprises a reservoir (e.g., a chamber or a conduit) adapted to containa coolant. The coolant flows through the reservoir near the scalp 30.The scalp 30 heats the coolant, which flows away from the scalp 30,thereby removing heat from the scalp 30 by active cooling. The coolantin certain embodiments circulates between the element 50 and a heattransfer device, such as a chiller, whereby the coolant is heated by thescalp 30 and is cooled by the heat transfer device. Exemplary materialsfor the coolant include, but are not limited to, water or air.

In certain embodiments, the element 50 comprises a container 51 (e.g., aflexible bag) coupled to an inlet conduit 52 and an outlet conduit 53,as schematically illustrated in FIG. 3. A flowing material (e.g., water,air, or glycerol) can flow into the container 51 from the inlet conduit52, absorb heat from the scalp 30, and flow out of the container 51through the outlet conduit 53. Certain such embodiments can provide amechanical fit of the container 51 to the scalp 30 and sufficientthermal coupling to prevent excessive heating of the scalp 30 by thelight. In certain embodiments, the container 51 can be disposable andreplacement containers 51 can be used for subsequent patients.

In still other embodiments, the element 50 comprises a container (e.g.,a flexible bag) containing a material which does not flow out of thecontainer but is thermally coupled to the scalp 30 so as to remove heatfrom the scalp 30 by passive cooling. Exemplary materials include, butare not limited to, water, glycerol, and gel. In certain suchembodiments, the non-flowing material can be pre-cooled (e.g., byplacement in a refrigerator) prior to the phototherapy treatment tofacilitate cooling of the scalp 30.

In certain embodiments, the element 50 is adapted to apply pressure toat least a portion of the scalp 30. By applying sufficient pressure, theelement 50 can blanch the portion of the scalp 30 by forcing at leastsome blood out the optical path of the light energy. The blood removalresulting from the pressure applied by the element 50 to the scalp 30decreases the corresponding absorption of the light energy by blood inthe scalp 30. As a result, temperature increases due to absorption ofthe light energy by blood at the scalp 30 are reduced. As a furtherresult, the fraction of the light energy transmitted to the subdermaltarget tissue of the brain 20 is increased.

FIGS. 4A and 4B schematically illustrate embodiments of the element 50adapted to facilitate the blanching of the scalp 30. In thecross-sectional view of a portion of the therapy apparatus 10schematically illustrated in FIG. 4A, certain element portions 72contact the patient's scalp 30 and other element portions 74 are spacedaway from the scalp 30. The element portions 72 contacting the scalp 30provide an optical path for light to propagate from the light source 40to the scalp 30. The element portions 72 contacting the scalp 30 alsoapply pressure to the scalp 30, thereby forcing blood out from beneaththe element portion 72. FIG. 4B schematically illustrates a similar viewof an embodiment in which the light source 40 comprises a plurality oflight sources 40 a, 40 b, 40 c.

FIG. 5A schematically illustrates one embodiment of the cross-sectionalong the line 4-4 of FIG. 4B. The element portions 72 contacting thescalp 30 comprise ridges extending along one direction, and the elementportions 74 spaced away from the scalp 30 comprise troughs extendingalong the same direction. In certain embodiments, the ridges aresubstantially parallel to one another and the troughs are substantiallyparallel to one another. FIG. 5B schematically illustrates anotherembodiment of the cross-section along the line 4-4 of FIG. 4B. Theelement portions 72 contacting the scalp 30 comprise a plurality ofprojections in the form of a grid or array. More specifically, theportions 72 are rectangular and are separated by element portions 74spaced away from the scalp 30, which form troughs extending in twosubstantially perpendicular directions. The portions 72 of the element50 contacting the scalp 30 can be a substantial fraction of the totalarea of the element 50 or of the scalp 30.

FIGS. 6A-6C schematically illustrate an embodiment in which the lightsources 40 are spaced away from the scalp 30. In certain suchembodiments, the light emitted by the light sources 40 propagates fromthe light sources 40 through the scalp 30 to the brain 20 and dispersesin a direction generally parallel to the scalp 30, as shown in FIG. 6A.The light sources 40 are preferably spaced sufficiently far apart fromone another such that the light emitted from each light source 40overlaps with the light emitted from the neighboring light sources 40 atthe brain 20. FIG. 6B schematically illustrates this overlap as theoverlap of circular spots 42 at a reference depth at or below thesurface of the brain 20. FIG. 6C schematically illustrates this overlapas a graph of the power density at the reference depth of the brain 20along the line L-L of FIGS. 6A and 6B. Summing the power densities fromthe neighboring light sources 40 (shown as a dashed line in FIG. 6C)serves to provide a more uniform light distribution at the tissue to betreated. In such embodiments, the summed power density is preferablyless than a damage threshold of the brain 20 and above an efficacythreshold.

In certain embodiments, the element 50 is adapted to diffuse the lightprior to reaching the scalp 30. FIGS. 7A and 7B schematically illustratethe diffusive effect on the light by the element 50. An exemplary energydensity profile of the light emitted by a light source 40, asillustrated by FIG. 7A, is peaked at a particular emission angle. Afterbeing diffused by the element 50, as illustrated by FIG. 7B, the energydensity profile of the light does not have a substantial peak at anyparticular emission angle, but is substantially evenly distributed amonga range of emission angles. By diffusing the light emitted by the lightsource 40, the element 50 distributes the light energy substantiallyevenly over the area to be illuminated, thereby inhibiting “hot spots”which would otherwise create temperature increases at the scalp 30. Inaddition, by diffusing the light prior to its reaching the scalp 30, theelement 50 can effectively increase the spot size of the light impingingthe scalp 30, thereby advantageously lowering the power density at thescalp 30, as described more fully below. In addition, in embodimentswith multiple light sources 40, the element 50 can diffuse the light toalter the total light output distribution to reduce inhomogeneities.

In certain embodiments, the element 50 provides sufficient diffusion ofthe light such that the power density of the light is less than amaximum tolerable level of the scalp 30 and brain 20. In certain otherembodiments, the element 50 provides sufficient diffusion of the lightsuch that the power density of the light equals a therapeutic value atthe target tissue. The element 50 can comprise exemplary diffusersincluding, but are not limited to, holographic diffusers such as thoseavailable from Physical Optics Corp. of Torrance, Calif. and DisplayOptics P/N SN1333 from Reflexite Corp. of Avon, Conn.

Power Density

Phototherapy for the treatment of stroke is based in part on thediscovery that power density (i.e., power per unit area or number ofphotons per unit area per unit time) and energy density (i.e., energyper unit area or number of photons per unit area) of the light energyapplied to tissue appear to be significant factors in determining therelative efficacy of low level phototherapy. This discovery isparticularly applicable with respect to treating and saving survivingbut endangered neurons in a zone of danger surrounding the primaryinfarct after a stroke or cerebrovascular accident (CVA). Preferredmethods described herein are based at least in part on the finding that,given a selected wavelength of light energy, it is the power densityand/or the energy density of the light delivered to tissue (as opposedto the total power or total energy delivered to the tissue) that appearsto be important factors in determining the relative efficacy ofphototherapy.

Without being bound by theory, it is believed that light energydelivered within a certain range of power densities and energy densitiesprovides the desired biostimulative effect on the intracellularenvironment, such that proper function is returned to previouslynonfunctioning or poorly functioning mitochondria in at-risk neurons.The biostimulative effect may include interactions with chromophoreswithin the target tissue, which facilitate production of ATP therebyfeeding energy to injured cells which have experienced decreased bloodflow due to the stroke. Because strokes correspond to blockages or otherinterruptions of blood flow to portions of the brain, it is thought thatany effects of increasing blood flow by phototherapy are of lessimportance in the efficacy of phototherapy for stroke victims. Furtherinformation regarding the role of power density and exposure time isdescribed by Hans H. F. I. van Breugel and P. R. Dop Bär in “PowerDensity and Exposure Time of He—Ne Laser Irradiation Are More ImportantThan Total Energy Dose in Photo-Biomodulation of Human Fibroblasts InVitro,” Lasers in Surgery and Medicine, Volume 12, pp. 528-537 (1992),which is incorporated in its entirety by reference herein.

The significance of the power density used in phototherapy hasramifications with regard to the devices and methods used inphototherapy of brain tissue, as schematically illustrated by FIGS. 8Aand 8B, which show the effects of scattering by intervening tissue.Further information regarding the scattering of light by tissue isprovided by V. Tuchin in “Tissue Optics: Light Scattering Methods andInstruments for Medical Diagnosis,” SPIE Press (2000), Bellingham,Wash., pp. 3-11, which is incorporated in its entirety by referenceherein.

FIG. 8A schematically illustrates a light beam 80 impinging a portion 90of a patient's scalp 30 and propagating through the patient's head toirradiate a portion 100 of the patient's brain tissue 20. In theexemplary embodiment of FIG. 8A, the light beam 80 impinging the scalp30 is collimated and has a circular cross-section with a radius of 2 cmand a cross-sectional area of approximately 12.5 cm². For comparisonpurposes, FIG. 8B schematically illustrates a light beam 82 having asignificantly smaller cross-section impinging a smaller portion 92 ofthe scalp 30 to irradiate a portion 102 of the brain tissue 20. Thelight beam 82 impinging the scalp 30 in FIG. 8B is collimated and has acircular cross-section with a radius of 1 cm and a cross-sectional areaof approximately 3.1 cm². The collimations, cross-sections, and radii ofthe light beams 80, 82 illustrated in FIGS. 8A and 8B are exemplary;other light beams with other parameters are also compatible withembodiments described herein. In particular, similar considerationsapply to focussed beams or diverging beams, as they are similarlyscattered by the intervening tissue.

As shown in FIGS. 8A and 8B, the cross-sections of the light beams 80,82 become larger while propagating through the head due to scatteringfrom interactions with tissue of the head. Assuming that the angle ofdispersion is 15 degrees and the irradiated brain tissue 20 is 2.5 cmbelow the scalp 30, the resulting area of the portion 100 of braintissue 20 irradiated by the light beam 80 in FIG. 8A is approximately22.4 cm². Similarly, the resulting area of the portion 102 of braintissue 20 irradiated by the light beam 82 in FIG. 8B is approximately8.8 cm².

Irradiating the portion 100 of the brain tissue 20 with a power densityof 10 mW/cm² corresponds to a total power within the portion 100 ofapproximately 224 mW (10 mW/cm²×22.4 cm²). Assuming only approximately5% of the light beam 80 is transmitted between the scalp 30 and thebrain tissue 20, the incident light beam 80 at the scalp 30 will have atotal power of approximately 4480 mW (224 mW/0.05) and a power densityof approximately 358 mW/cm² (4480 mW/12.5 cm²). Similarly, irradiatingthe portion 102 of the brain tissue 20 with a power density of 10 mW/cm²corresponds to a total power within the portion 102 of approximately 88mW (10 mW/cm²×8.8 cm²), and with the same 5% transmittance, the incidentlight beam 82 at the scalp 30 will have a total power of approximately1760 mW (88 mW/0.05) and a power density of approximately 568 mW/cm²(1760 mW/3.1 cm²). These calculations are summarized in Table 1. TABLE 12 cm Spot Size 1 cm Spot Size (FIG. 8A) (FIG. 8B) Scalp: Area 12.5 cm²3.1 cm² Total power 4480 mW 1760 mW Power density 358 mW/cm² 568 mW/cm²Brain: Area 22.4 cm² 8.8 cm² Total power 224 mW 88 mW Power density 10mW/cm² 10 mW/cm²

These exemplary calculations illustrate that to obtain a desired powerdensity at the brain 20, higher total power at the scalp 30 can be usedin conjunction with a larger spot size at the scalp 30. Thus, byincreasing the spot size at the scalp 30, a desired power density at thebrain 20 can be achieved with lower power densities at the scalp 30which can reduce the possibility of overheating the scalp 30. In certainembodiments, the light can be directed through an aperture to define theillumination of the scalp 30 to a selected smaller area.

Light Source

The light source 40 preferably generates light in the visible tonear-infrared wavelength range. In certain embodiments, the light source40 comprises one or more laser diodes, which each provide coherentlight. In embodiments in which the light from the light source 40 iscoherent, the emitted light may produce “speckling” due to coherentinterference of the light. This speckling comprises intensity spikeswhich are created by constructive interference and can occur inproximity to the target tissue being treated. For example, while theaverage power density may be approximately 10 mW/cm², the power densityof one such intensity spike in proximity to the brain tissue to betreated may be approximately 300 mW/cm². In certain embodiments, thisincreased power density due to speckling can improve the efficacy oftreatments using coherent light over those using incoherent light forillumination of deeper tissues.

In other embodiments, the light source 40 provides incoherent light.Exemplary light sources 40 of incoherent light include, but are notlimited to, incandescent lamps or light-emitting diodes. A heat sink canbe used with the light source 40 (for either coherent or incoherentsources) to remove heat from the light source 40 and to inhibittemperature increases at the scalp 30.

In certain embodiments, the light source 40 generates light which issubstantially monochromatic (i.e., light having one wavelength, or lighthaving a narrow band of wavelengths). So that the amount of lighttransmitted to the brain is maximized, the wavelength of the light isselected in certain embodiments to be at or near a transmission peak (orat or near an absorption minimum) for the intervening tissue. In certainsuch embodiments, the wavelength corresponds to a peak in thetransmission spectrum of tissue at about 820 nanometers. In otherembodiments, the wavelength of the light is preferably between about 630nanometers and about 1064 nanometers, more preferably between about 780nanometers and about 840, nanometers, and most preferably includeswavelengths of about 790, 800, 810, 820, or 830 nanometers. It has alsobeen found that an intermediate wavelength of about 739 nanometersappears to be suitable for penetrating the skull, although otherwavelengths are also suitable and may be used.

In other embodiments, the light source 40 generates light having aplurality of wavelengths. In certain such embodiments, each wavelengthis selected so as to work with one or more chromophores within thetarget tissue. Without being bound by theory, it is believed thatirradiation of chromophores increases the production of ATP in thetarget tissue, thereby producing beneficial effects. In certainembodiments, the light source 40 is adapted to generate light having afirst wavelength concurrently with light having a second wavelength. Incertain other embodiments, the light source 40 is adapted to generatelight having a first wavelength sequentially with light having a secondwavelength.

In certain embodiments, the light source 40 includes at least onecontinuously emitting GaAlAs laser diode having a wavelength of about830 nanometers. In another embodiment, the light source 40 comprises alaser source having a wavelength of about 808 nanometers. In still otherembodiments, the light source 40 includes at least one vertical cavitysurface-emitting laser (VCSEL) diode. Other light sources 40 compatiblewith embodiments described herein include, but are not limited to,light-emitting diodes (LEDs) and filtered lamps.

The light source 40 is capable of emitting light energy at a powersufficient to achieve a predetermined power density at the subdermaltarget tissue (e.g., at a depth of approximately 2 centimeters from thedura). It is presently believed that phototherapy of tissue is mosteffective when irradiating the target tissue with power densities oflight of at least about 0.01 mW/cm² and up to about 1 W/cm². In variousembodiments, the subsurface power density is at least about 0.01, 0.05,0.1, 0.5, 1, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, or 90 mW/cm²,respectively, depending on the desired clinical performance. In certainembodiments, the subsurface power density is preferably about 0.01mW/cm² to about 100 mW/cm², more preferably about 0.01 mW/cm² to about50 mW/cm², and most preferably about 2 mW/cm² to about 20 mW/cm². It isbelieved that these subsurface power densities are especially effectiveat producing the desired biostimulative effects on the tissue beingtreated.

Taking into account the attenuation of energy as it propagates from theskin surface, through body tissue, bone, and fluids, to the subdermaltarget tissue, surface power densities preferably between about 10mW/cm² to about 10 W/cm², or more preferably between about 100 mW/cm² toabout 500 mW/cm², will typically be used to attain the selected powerdensities at the subdermal target tissue. To achieve such surface powerdensities, the light source 40 is preferably capable of emitting lightenergy having a total power output of at least about 25 mW to about 100W. In various embodiments, the total power output is limited to be nomore than about 30, 50, 75, 100, 150, 200, 250, 300, 400, or 500 mW,respectively. In certain embodiments, the light source 40 comprises aplurality of sources used in combination to provide the total poweroutput. The actual power output of the light source 40 is preferablycontrollably variable. In this way, the power of the light energyemitted can be adjusted in accordance with a selected power density atthe subdermal tissue being treated.

Certain embodiments utilize a light source 40 that includes only asingle laser diode that is capable of providing about 25 mW to about 100W of total power output at the skin surface. In certain suchembodiments, the laser diode can be optically coupled to the scalp 30via an optical fiber or can be configured to provide a sufficientlylarge spot size to avoid power densities which would burn or otherwisedamage the scalp 30. In other embodiments, the light source 40 utilizesa plurality of sources (e.g., laser diodes) arranged in a grid or arraythat together are capable of providing at least about 25 mW to about 100W of total power output at the skin surface. The light source 40 ofother embodiments may also comprise sources having power capacitiesoutside of these limits.

FIG. 9A schematically illustrates another embodiment of the therapyapparatus 10 which comprises the cap 60 and a light source comprising alight-emitting blanket 110. FIG. 9B schematically illustrates anembodiment of the blanket 110 comprising a flexible substrate 111 (e.g.,flexible circuit board), a power conduit interface 112, and a sheetformed by optical fibers 114 positioned in a fan-like configuration.FIG. 9C schematically illustrates an embodiment of the blanket 110comprising a flexible substrate 111, a power conduit interface 112, anda sheet formed by optical fibers 114 woven into a mesh. The blanket 110is preferably positioned within the cap 60 so as to cover an area of thescalp 30 corresponding to a portion of the brain 20 to be treated.

In certain such embodiments, the power conduit interface 112 is adaptedto be coupled to an optical fiber conduit 64 which provides opticalpower to the blanket 110. The optical power interface 112 of certainembodiments comprises a beam splitter or other optical device whichdistributes the incoming optical power among the various optical fibers114. In other embodiments, the power conduit interface 112 is adapted tobe coupled to an electrical conduit which provides electrical power tothe blanket 110. In certain such embodiments, the power conduitinterface 112 comprises one or more laser diodes, the output of which isdistributed among the various optical fibers 114 of the blanket 110. Incertain other embodiments, the blanket 110 comprises anelectroluminescent sheet which responds to electrical signals from thepower conduit interface 112 by emitting light. In such embodiments, thepower conduit interface 112 comprises circuitry adapted to distributethe electrical signals to appropriate portions of the electroluminescentsheet.

The side of the blanket 110 nearer the scalp 30 is preferably providedwith a light scattering surface, such as a roughened surface to increasethe amount of light scattered out of the blanket 110 towards the scalp30. The side of the blanket 110 further from the scalp 30 is preferablycovered by a reflective coating so that light emitted away from thescalp 30 is reflected back towards the scalp 30. This configuration issimilar to configurations used for the “back illumination” ofliquid-crystal displays (LCDs). Other configurations of the blanket 110are compatible with embodiments described herein.

In certain embodiments, the light source 40 generates light which causeeye damage if viewed by an individual. In such embodiments, theapparatus 50 can be configured to provide eye protection so as to avoidviewing of the light by individuals. For example, opaque materials canbe appropriately placed to block the light from being viewed directly.In addition, interlocks can be provided so that the light source 40 isnot activated unless the apparatus 50 is in place, or other appropriatesafety measures are taken.

Light Delivery Apparatuses

The phototherapy methods for the treatment of stroke described hereinmay be practiced and described using, for example, a low level lasertherapy apparatus such as that shown and described in U.S. Pat. No.6,214,035, U.S. Pat. No. 6,267,780, U.S. Pat. No. 6,273,905 and U.S.Pat. No. 6,290,714, which are all incorporated in their entirety byreference herein, as are the references incorporated by referencetherein.

Another suitable phototherapy apparatus in accordance with embodimentsdescribed here is illustrated in FIG. 10. The illustrated therapyapparatus 10 includes a light source 40, an element 50, and a flexiblestrap 120 adapted for securing the therapy apparatus 10 over an area ofthe patient's head. The light source 40 can be disposed on the strap 120itself, or in a housing 122 coupled to the strap 120. The light source40 preferably comprises a plurality of diodes 40 a, 40 b, . . . capableof emitting light energy having a wavelength in the visible tonear-infrared wavelength range. The element 50 is adapted to bepositioned between the light source 40 and the patient's scalp 30.

The therapy apparatus 10 further includes a power supply (not shown)operatively coupled to the light source 40, and a programmablecontroller 126 operatively coupled to the light source 40 and to thepower supply. The programmable controller 126 is configured to controlthe light source 40 so as to deliver a predetermined power density tothe brain tissue 20. In certain embodiments, as schematicallyillustrated in FIG. 10 the light source 40 comprises the programmablecontroller 126. In other embodiments the programmable controller 126 isa separate component of the therapy apparatus 10.

In certain embodiments, the strap 120 comprises a loop of elastomericmaterial sized appropriately to fit snugly onto the patient's scalp 30.In other embodiments, the strap 120 comprises an elastomeric material towhich is secured any suitable securing means 130, such as mating Velcrostrips, buckles, snaps, hooks, buttons, ties, or the like. The preciseconfiguration of the strap 120 is subject only to the limitation thatthe strap 120 is capable of maintaining the light source 40 in aselected position so that light energy emitted by the light source 40 isdirected towards the targeted brain tissue 20.

In the exemplary embodiment illustrated in FIG. 10, the housing 122comprises a layer of flexible plastic or fabric that is secured to thestrap 120. In other embodiments, the housing 122 comprises a plate or anenlarged portion of the strap 120. Various strap configurations andspatial distributions of the light sources 40 are compatible withembodiments described herein so that the therapy apparatus 10 can treatselected portions of brain tissue.

In still other embodiments, the therapy apparatus 10 for delivering thelight energy includes a handheld probe 140, as schematically illustratedin FIG. 11. The probe 140 includes a light source 40 and an element 50as described herein.

FIG. 12 is a block diagram of a control circuit 200 comprising aprogrammable controller 126 according to embodiments described herein.The control circuit 200 is configured to adjust the power of the lightenergy emitted by the light source 40 to generate a predeterminedsurface power density at the scalp 30 corresponding to a predeterminedenergy delivery profile, such as a predetermined subsurface powerdensity, to the target area of the brain 20.

In certain embodiments, the programmable controller 126 comprises alogic circuit 210, a clock 212 coupled to the logic circuit 210, and aninterface 214 coupled to the logic circuit 210. The clock 212 of certainembodiments provides a timing signal to the logic circuit 210 so thatthe logic circuit 210 can monitor and control timing intervals of theapplied light. Examples of timing intervals include, but are not limitedto, total treatment times, pulsewidth times for pulses of applied light,and time intervals between pulses of applied light. In certainembodiments, the light sources 40 can be selectively turned on and offto reduce the thermal load on the scalp 30 and to deliver a selectedpower density to particular areas of the brain 20.

The interface 214 of certain embodiments provides signals to the logiccircuit 210 which the logic circuit 210 uses to control the appliedlight. The interface 214 can comprise a user interface or an interfaceto a sensor monitoring at least one parameter of the treatment. Incertain such embodiments, the programmable controller 126 is responsiveto signals from the sensor to preferably adjust the treatment parametersto optimize the measured response. The programmable controller 126 canthus provide closed-loop monitoring and adjustment of various treatmentparameters to optimize the phototherapy. The signals provided by theinterface 214 from a user are indicative of parameters that may include,but are not limited to, patient characteristics (e.g., skin type, fatpercentage), selected applied power densities, target time intervals,and power density/timing profiles for the applied light.

In certain embodiments, the logic circuit 210 is coupled to a lightsource driver 220. The light source driver 220 is coupled to a powersupply 230, which in certain embodiments comprises a battery and inother embodiments comprises an alternating current source. The lightsource driver 220 is also coupled to the light source 40. The logiccircuit 210 is responsive to the signal from the clock 212 and to userinput from the user interface 214 to transmit a control signal to thelight source driver 220. In response to the control signal from thelogic circuit 210, the light source driver 220 adjust and controls thepower applied to the light sources 40. Other control circuits besidesthe control circuit 200 of FIG. 12 are compatible with embodimentsdescribed herein.

In certain embodiments, the logic circuit 110 is responsive to signalsfrom a sensor monitoring at least one parameter of the treatment tocontrol the applied light. For example, certain embodiments comprise atemperature sensor thermally coupled to the scalp 30 to provideinformation regarding the temperature of the scalp 30 to the logiccircuit 210. In such embodiments, the logic circuit 210 is responsive tothe information from the temperature sensor to transmit a control signalto the light source driver 220 so as to adjust the parameters of theapplied light to maintain the scalp temperature below a predeterminedlevel. Other embodiments include exemplary biomedical sensors including,but not limited to, a blood flow sensor, a blood gas (e.g., oxygenation)sensor, an ATP production sensor, or a cellular activity sensor. Suchbiomedical sensors can provide real-time feedback information to thelogic circuit 210. In certain such embodiments, the logic circuit 110 isresponsive to signals from the sensors to preferably adjust theparameters of the applied light to optimize the measured response. Thelogic circuit 110 can thus provide closed-loop monitoring and adjustmentof various parameters of the applied light to optimize the phototherapy.

In certain embodiments, as schematically illustrated in FIG. 13, thetherapy apparatus 310 comprises a light source 340 adapted to irradiatea portion of the patient's brain 20 with an efficacious power densityand wavelength of light. The therapy apparatus 310 further comprises acontroller 360 for energizing said light source 340, so as toselectively produce a plurality of different irradiation patterns on thepatient's scalp 30. Each of the irradiation patterns is comprised of aleast one illuminated area that is small compared to the patient's scalp30, and at least one non-illuminated area.

In certain embodiments, the light source 340 includes an apparatus foradjusting the emitted light to irradiate different portions of the scalp30. In certain such embodiments, the apparatus physically moves thelight source 40 relative to the scalp 30. In other embodiments, theapparatus does not move the light source 40, but redirects the emittedlight to different portions of the scalp 30. In an exemplary embodiment,as schematically illustrated in FIG. 14, the light source 340 comprisesa laser diode 342 and a galvometer 344, both of which are electricallycoupled to the controller 360. The galvometer 344 comprises a mirror 346mounted onto an assembly 348 which is adjustable by a plurality ofmotors 350. Light emitted by the laser diode 342 is directed toward themirror 346 and is reflected to selected portions of the patient's scalp30 by selectively moving the mirror 346 and selectively activating thelaser diode 342. In certain embodiments, the therapy apparatus 310comprises an element 50 adapted to inhibit temperature increases at thescalp 30 as described herein.

FIG. 15A schematically illustrates an irradiation pattern 370 inaccordance with embodiments described herein. The irradiation pattern370 comprises at least one illuminated area 372 and at least onenon-illuminated area 374. In certain embodiments, the irradiationpattern 370 is generated by scanning the mirror 346 so that the lightimpinges the patient's scalp 30 in the illuminated area 372 but not inthe non-illuminated area 374. Certain embodiments modify the illuminatedarea 372 and the non-illuminated area 374 as a function of time.

This selective irradiation can be used to reduce the thermal load onparticular locations of the scalp 30 by moving the light from oneilluminated area 372 to another. For example, by irradiating the scalp30 with the irradiation pattern 370 schematically illustrated in FIG.15A, the illuminated areas 372 of the scalp 30 are heated by interactionwith the light, and the non-illuminated areas 374 are not heated. Bysubsequently irradiating the scalp 30 with the complementary irradiationpattern 370 ′ schematically illustrated in FIG. 15B, the previouslynon-illuminated areas 374 are now illuminated areas 372′, and thepreviously illuminated areas 372 are now non-illuminated areas 374′. Acomparison of the illuminated areas 372 of the irradiation pattern 370of FIG. 15A with the illuminated area 372′ of the irradiation pattern370′ of FIG. 15B shows that the illuminated areas 372, 372′ do notsignificantly overlap one another. In this way, the thermal load at thescalp 30 due to the absorption of the light can be distributed acrossthe scalp 30, thereby avoiding unduly heating one or more portions ofthe scalp 30.

Methods of Light Delivery

Preferred methods of phototherapy are based at least in part on thefinding described above that, for a selected wavelength, the powerdensity (light intensity or power per unit area, in W/cm²) or the energydensity (energy per unit area, in J/cm², or power density multiplied bythe exposure time) of the light energy delivered to tissue is animportant factor in determining the relative efficacy of thephototherapy, and efficacy is not as directly related to the total poweror the total energy delivered to the tissue. In the methods describedherein, power density or energy density as delivered to a portion of thepatient's brain 20, which can include the area of infarct after astroke, appears to be important factors in using phototherapy to treatand save surviving but endangered neurons in a zone of dangersurrounding the infarcted area. Certain embodiments apply optimal powerdensities or energy densities to the intended target tissue, withinacceptable margins of error.

As used herein, the term “neurodegeneration” refers to the process ofcell destruction resulting from primary destructive events such asstroke or CVA, as well as from secondary, delayed and progressivedestructive mechanisms that are invoked by cells due to the occurrenceof the primary destructive event. Primary destructive events includedisease processes or physical injury or insult, including stroke, butalso include other diseases and conditions such as multiple sclerosis,amylotrophic lateral sclerosis, epilepsy, Alzheimer's disease, dementiaresulting from other causes such as AIDS, cerebral ischemia includingfocal cerebral ischemia, and physical trauma such as crush orcompression injury in the CNS, including a crush or compression injuryof the brain, spinal cord, nerves or retina, or any acute injury orinsult producing neurodegeneration. Secondary destructive mechanismsinclude any mechanism that leads to the generation and release ofneurotoxic molecules, including apoptosis, depletion of cellular energystores because of changes in mitochondrial membrane permeability,release or failure in the reuptake of excessive glutamate, reperfusioninjury, and activity of cytokines and inflammation. Both primary andsecondary mechanisms contribute to forming a “zone of danger” forneurons, wherein the neurons in the zone have at least temporarilysurvived the primary destructive event, but are at risk of dying due toprocesses having delayed effect.

As used herein, the term “neuroprotection” refers to a therapeuticstrategy for slowing or preventing the otherwise irreversible loss ofneurons due to neurodegeneration after a primary destructive event,whether the neurodegeneration loss is due to disease mechanismsassociated with the primary destructive event or secondary destructivemechanisms.

As used herein, the term “neuroprotective-effective” as used hereinrefers to a characteristic of an amount of light energy, wherein theamount is a power density of the light energy measured in mW/cm². Aneuroprotective-effective amount of light energy achieves the goal ofpreventing, avoiding, reducing, or eliminating neurodegeneration.

Thus, a method for the treatment of stroke in a patient in need of suchtreatment involves delivering a neuroprotective-effective amount oflight energy having a wavelength in the visible to near-infraredwavelength range to a target area of the patient's brain 20. In certainembodiments, the target area of the patient's brain 20 includes the areaof infarct, i.e. to neurons within the “zone of danger.” In otherembodiments, the target area includes portions of the brain 20 notwithin the zone of danger. Without being bound by theory, it is believedthat irradiation of healthy tissue in proximity to the zone of dangerincreases the production of ATP and copper ions in the healthy tissueand which then migrate to the injured cells within the regionsurrounding the infarct, thereby producing beneficial effects.Additional information regarding the biomedical mechanisms or reactionsinvolved in phototherapy is provided by Tiina I. Karu in “Mechanisms ofLow-Power Laser Light Action on Cellular Level”, Proceedings of SPIEVol. 4159 (2000), Effects of Low-Power Light on Biological Systems V,Ed. Rachel Lubart, pp. 1-17, which is incorporated in its entirety byreference herein.

In certain embodiments, delivering the neuroprotective amount of lightenergy includes selecting a surface power density of the light energy atthe scalp 30 corresponding to the predetermined power density at thetarget area of the brain 20. As described above, light propagatingthrough tissue is scattered and absorbed by the tissue. Calculations ofthe power density to be applied to the scalp 30 so as to deliver apredetermined power density to the selected target area of the brain 20preferably take into account the attenuation of the light energy as itpropagates through the skin and other tissues, such as bone and braintissue. Factors known to affect the attenuation of light propagating tothe brain 20 from the scalp 30 include, but are not limited to, skinpigmentation, the presence and color of hair over the area to betreated, amount of fat tissue, the presence of bruised tissue, skullthickness, and the location of the target area of the brain 20,particularly the depth of the area relative to the surface of the scalp30. For example, to obtain a desired power density of 50 mW/cm² in thebrain 20 at a depth of 3 cm below the surface of the scalp 30,phototherapy may utilize an applied power density of 500 mW/cm². Thehigher the level of skin pigmentation, the higher the power densityapplied to the scalp 30 to deliver a predetermined power density oflight energy to a subsurface site of the brain 20.

In certain embodiments, treating a patient suffering from the effects ofstroke comprises placing the therapy apparatus 10 in contact with thescalp 30 and adjacent the target area of the patient's brain 20. Thetarget area of the patient's brain 20 can be previously identified suchas by using standard medical imaging techniques. In certain embodiments,treatment further includes calculating a surface power density at thescalp 30 which corresponds to a preselected power density at the targetarea of the patient's brain 20. The calculation of certain embodimentsincludes factors that affect the penetration of the light energy andthus the power density at the target area. These factors include, butare not limited to, the thickness of the patient's skull, type of hairand hair coloration, skin coloration and pigmentation, patient's age,patient's gender, and the distance to the target area within the brain20. The power density and other parameters of the applied light are thenadjusted according to the results of the calculation.

The power density selected to be applied to the target area of thepatient's brain 20 depends on a number of factors, including, but notlimited to, the wavelength of the applied light, the type of CVA(ischemic or hemorrhagic), and the patient's clinical condition,including the extent of the affected brain area. The power density oflight energy to be delivered to the target area of the patient's brain20 may also be adjusted to be combined with any other therapeutic agentor agents, especially pharmaceutical neuroprotective agents, to achievethe desired biological effect. In such embodiments, the selected powerdensity can also depend on the additional therapeutic agent or agentschosen.

In preferred embodiments, the treatment proceeds continuously for aperiod of about 10 seconds to about 2 hours, more preferably for aperiod of about 1 to about 10 minutes, and most preferably for a periodof about 1 to 5 minutes. In other embodiments, the light energy ispreferably delivered for at least one treatment period of at least aboutfive minutes, and more preferably for at least one treatment period ofat least ten minutes. The light energy can be pulsed during thetreatment period or the light energy can be continuously applied duringthe treatment period.

In certain embodiments, the treatment may be terminated after onetreatment period, while in other embodiments, the treatment may berepeated for at least two treatment periods. The time between subsequenttreatment periods is preferably at least about five minutes, morepreferably at least about 1 to 2 days, and most preferably at leastabout one week. In certain embodiments in which treatment is performedover the course of multiple days, the apparatus 10 is wearable overmultiple concurrent days (e.g., embodiments of FIGS. 1, 3, 9A, 10, and13). The length of treatment time and frequency of treatment periods candepend on several factors, including the functional recovery of thepatient and the results of imaging analysis of the infarct. In certainembodiments, one or more treatment parameters can be adjusted inresponse to a feedback signal from a device (e.g., magnetic resonanceimaging) monitoring the patient.

During the treatment, the light energy may be continuously provided, orit may be pulsed. If the light is pulsed, the pulses are preferably atleast about 10 nanosecond long and occur at a frequency of up to about100 kHz. Continuous wave light may also be used.

The thrombolytic therapies currently in use for treatment of stroke aretypically begun within a few hours of the stroke. However, many hoursoften pass before a person who has suffered a stroke receives medicaltreatment, so the short time limit for initiating thrombolytic therapyexcludes many patients from treatment. In contrast, phototherapytreatment of stroke appears to be more effective if treatment begins noearlier than several hours after the ischemic event has occurred.Consequently, the present methods of phototherapy may be used to treat agreater percentage of stroke patients.

In certain embodiments, a method provides a neuroprotective effect in apatient that had an ischemic event in the brain. The method comprisesidentifying a patient who has experienced an ischemic event in thebrain. The method further comprises estimating the time of the ischemicevent. The method further comprises commencing administration of aneuroprotective effective amount of light energy to the brain. Theadministration of the light energy is commenced no less than about twohours following the time of the ischemic event. In certain embodiments,phototherapy treatment can be efficaciously performed preferably within24 hours after the ischemic event occurs, and more preferably no earlierthan two hours following the ischemic event, still more preferably noearlier than three hours following the ischemic event, and mostpreferably no earlier than five hours following the ischemic event. Incertain embodiments, one or more of the treatment parameters can bevaried depending on the amount of time that has elapsed since theischemic event.

Without being bound by theory, it is believed that the benefit indelaying treatment occurs because of the time needed for induction ofATP production, and/or the possible induction of angiogenesis in theregion surrounding the infarct. Thus, in accordance with one preferredembodiment, the phototherapy for the treatment of stroke occurspreferably about 6 to 24 hours after the onset of stroke symptoms, morepreferably about 12 to 24 hours after the onset of symptoms. It isbelieved, however, that if treatment begins after about 2 days, itseffectiveness will be greatly reduced.

EXAMPLE

An in vitro experiment was done to demonstrate one effect ofphototherapy on neurons, namely the effect on ATP production. NormalHuman Neural Progenitor (NHNP) cells were obtained cryopreserved throughClonetics of Baltimore, Md., catalog # CC-2599. The NHNP cells werethawed and cultured on polyethyleneimine (PEI) with reagents providedwith the cells, following the manufacturers' instructions. The cellswere plated into 96 well plates (black plastic with clear bottoms,Becton Dickinson of Franklin Lakes, N.J.) as spheroids and allowed todifferentiate into mature neurons over a period of two weeks.

A Photo Dosing Assembly (PDA) was used to provide precisely metereddoses of laser light to the NHNP cells in the 96 well plates. The PDAincluded a Nikon Diaphot inverted microscope (Nikon of Melville, N.Y.)with a LUDL motorized x,y,z stage (Ludl Electronic Products ofHawthorne, N.Y.). An 808 nanometer laser was routed into the rearepi-fluorescent port on the microscope using a custom designed adapterand a fiber optic cable. Diffusing lenses were mounted in the path ofthe beam to create a “speckled” pattern, which was intended to mimic invivo conditions after a laser beam passed through human skin. The beamdiverged to a 25 millimeter diameter circle when it reached the bottomof the 96 well plates. This dimension was chosen so that a cluster offour adjacent wells could be lased at the same time. Cells were platedin a pattern such that a total of 12 clusters could be lased per 96 wellplate. Stage positioning was controlled by a Silicon Graphicsworkstation and laser timing was performed by hand using a digitaltimer. The measured power density passing through the plate for the NHNPcells was 50 mW/cm².

Two independent assays were used to measure the effects of 808 nanometerlaser light on the NHNP cells. The first was the CellTiter-GloLuminescent Cell Viability Assay (Promega of Madison, Wis.). This assaygenerates a “glow-type” luminescent signal produced by a luciferasereaction with cellular ATP. The CellTiter-Glo reagent is added in anamount equal to the volume of media in the well and results in celllysis followed by a sustained luminescent reaction that was measuredusing a Reporter luminometer (Turner Biosystems of Sunnyvale, Calif.).Amounts of ATP present in the NHNP cells were quantified in RelativeLuminescent Units (RLUs) by the luminometer.

The second assay used was the alamarBlue assay (Biosource of Camarillo,Calif.). The internal environment of a proliferating cell is morereduced than that of a non-proliferating cell. Specifically, the ratiosof NADPH/NADP, FADH/FAD, FMNH/FMN and NADH/NAD, increase duringproliferation. Laser irradiation is also thought to have an effect onthese ratios. Compounds such as alamarBlue are reduced by thesemetabolic intermediates and can be used to monitor cellular states. Theoxidization of alamarBlue is accompanied by a measurable shift in color.In its unoxidized state, alamarBlue appears blue; when oxidized, thecolor changes to red. To quantify this shift, a 340PC microplate readingspectrophotometer (Molecular Devices of Sunnyvale, Calif.) was used tomeasure the absorbance of a well containing NHNP cells, media andalamarBlue diluted 10% v/v. The absorbance of each well was measured at570 nanometers and 600 nanometers and the percent reduction ofalamarBlue was calculated using an equation provided by themanufacturer.

The two metrics described above, (RLUs and % Reduction) were then usedto compare NHNP culture wells that had been lased with 50 mW/cm² at awavelength of 808 nanometers. For the CellTiter-Glo assay, 20 wells werelased for 1 second and compared to an unlased control group of 20 wells.The CellTiter-Glo reagent was added 10 minutes after lasing completedand the plate was read after the cells had lysed and the luciferasereaction had stabilized. The average RLUs measured for the control wellswas 3808±3394 while the laser group showed a two-fold increase in ATPcontent to 7513±6109. The standard deviations were somewhat high due tothe relatively small number of NHNP cells in the wells (approximately100 per well from visual observation), but a student's unpaired t-testwas performed on the data with a resulting p-value of 0.02 indicatingthat the two-fold change is statistically significant.

The alamarBlue assay was performed with a higher cell density and alasing time of 5 seconds. The plating density (calculated to be between7,500-26,000 cells per well based on the certificate of analysisprovided by the manufacturer) was difficult to determine since some ofthe cells had remained in the spheroids and had not completelydifferentiated. Wells from the same plate can still be compared though,since plating conditions were identical. The alamarBlue was addedimmediately after lasing and the absorbance was measured 9.5 hourslater. The average measured values for percent reduction were 22% ±7.3%for the 8 lased wells and 12.4 %±5.9% for the 3 unlased control wells(p-value=0.076). These alamarBlue results support the earlier findingsin that they show a similar positive effect of the laser treatment onthe cells.

Increases in cellular ATP concentration and a more reduced state withinthe cell are both related to cellular metabolism and are considered tobe indications that the cell is viable and healthy. These results arenovel and significant in that they show the positive effects of laserirradiation on cellular metabolism in in-vitro neuronal cell cultures.

In certain embodiments, the phototherapy is combined with other types oftreatments for an improved therapeutic effect. Treatment can comprisedirecting light through the scalp of the patient to a target area of thebrain concurrently with applying an electromagnetic field to the brain.In such embodiments, the light has an efficacious power density at thetarget area and the electromagnetic field has an efficacious fieldstrength. For example, the apparatus 50 can also include systems forelectromagnetic treatment, e.g., as described in U.S. Pat. No. 6,042,531issued to Holcomb, which is incorporated in its entirety by referenceherein. In certain embodiments, the electromagnetic field comprises amagnetic field, while in other embodiments, the electromagnetic fieldcomprises a radio-frequency (RF) field. As another example, treatmentcan comprise directing an efficacious power density of light through thescalp of the patient to a target area of the brain concurrently withapplying an efficacious amount of ultrasonic energy to the brain. Such asystem can include systems for ultrasonic treatment, e.g., as describedin U.S. Pat. No. 5,954,470 issued to Fry et al., which is incorporatedin its entirety by reference herein.

The explanations and illustrations presented herein are intended toacquaint others skilled in the art with the invention, its principles,and its practical application. Those skilled in the art may adapt andapply the invention in its numerous forms, as may be best suited to therequirements of a particular use. Accordingly, the specific embodimentsof the present invention as set forth are not intended as beingexhaustive or limiting of the invention.

1. A therapy apparatus for treating a patient's brain, the therapyapparatus comprising: a light source having an output emission areapositioned to irradiate a target portion of the brain with light havinga wavelength between about 630 nanometers and about 1064 nanometers, thelight having an efficacious power density of at least about 1 mW/cm² atthe target portion; and a material interposed between the light sourceand the patient's scalp, the material being substantially transmissiveto the light and thermally conductive so as to absorb heat from thescalp.
 2. The therapy apparatus of claim 1, wherein the light passesthrough the material prior to reaching the scalp.
 3. The therapyapparatus of claim 1, wherein the material is adapted to contact thepatient's scalp.
 4. The therapy apparatus of claim 3, wherein thematerial is attached to the light source and is adapted to conform tothe scalp so as to position the light source relative to the scalp. 5.The therapy apparatus of claim 4, wherein the material is mechanicallyadjustable so as to adjust a position of the light source relative tothe scalp.
 6. The therapy apparatus of claim 4, wherein the material ismechanically adjustable so as to fit the therapy apparatus to the scalp.7. The therapy apparatus of claim 6, further comprising a bag containingthe material, the bag and the material adapted to conform to contours ofthe scalp.
 8. The therapy apparatus of claim 4, wherein at least aportion of the material is within an optical path of the light from thesource to the scalp.
 9. The therapy apparatus of claim 8, wherein thematerial is adapted to reduce back reflections of the light.
 10. Thetherapy apparatus of claim 9, wherein the material is adapted to fit tothe scalp so as to substantially reduce air gaps between the scalp andthe material in the optical path of the light.
 11. The therapy apparatusof claim 9, wherein the material has a refractive index whichsubstantially matches a refractive index of the scalp.
 12. The therapyapparatus of claim 1, wherein the material is pre-cooled prior totreatment of the brain.
 13. The therapy apparatus of claim 1, whereinthe material is adapted to apply pressure to at least a portion of thescalp, thereby blanching the portion of the scalp and decreasingabsorption of the light by blood in the scalp.
 14. The therapy apparatusof claim 1, wherein the material is adapted to diffuse the light priorto reaching the scalp.
 15. A method of irradiating a portion of braintissue of a patient, the method comprising: positioning a light sourceat a first position and directing light from the light source through afirst illuminated area of the patient's scalp to irradiate the portionwith light having a power density of at least about 1 mW/cm²; and movingthe light source from the first position to a second position anddirecting light from the light source through a second illuminated areaof the patient's scalp to irradiate the portion with light having apower density of at least about 1 mW/cm², the second illuminated areaseparated from the first illuminated area by at least onenon-illuminated area.
 16. A method of treating a portion of brain tissueof a patient, the method comprising: removing at least a portion of thehair from a patient's scalp from an area of the scalp; and introducinglight having an efficacious power density of at least about 1 mW/cm² atthe portion of brain tissue by directing light through the area of thescalp, wherein the light has a power density at the scalp below a damagethreshold of scalp tissue and has sufficient optical power at the scalpto achieve the efficacious power density at the portion of brain tissue.